Alzheimer's disease (AD) is the major cause of dementia in the elderly, with a US incidence of 5.4 million and an annual cost of $183 billion. There is no effective treatment. This proposal is in response to an NIA request for R21 high risk/high reward proposals to generate new AD drug discovery strategies. It focuses on current knowledge indicating that significant neuron damage in AD can be attributed to the impact of toxic Ab oligomers. These small diffusible molecules are distinct from amyloid plaques and are thought to instigate AD memory loss through their ability to target synapses and disrupt synaptic plasticity. Current efforts to prevent AD largely focus on metabolic inhibitors that block accumulation of the Ab monomer and on passive vaccines that remove either the monomer or its toxic assemblies. These efforts have not as yet been successful. This proposal introduces an alternative strategy that focuses on the first step in the mechanism of oligomer toxicity. To elici damage, oligomers must first bind to cellular receptors. These receptors mediate association of oligomers with particular neurons and transduce binding into synaptotoxic responses. Although receptor identity would be valuable for elucidating the mechanism of toxicity, it is feasible even without this knowledge to use oligomer-receptor binding as a target for drug discovery. What is required is an assay suitable for large- scale high-throughput screening (HTS) of binding antagonists. We propose a novel strategy to achieve this goal using an approach that generates artificial nanoscale membranes (Nanodiscs). This is a well-established methodology that has been adapted here to provide unbiased and functional soluble preparations of synaptic plasma membrane proteins. Binding of oligomers to synaptic plasma membrane (SPM) Nanodiscs has been demonstrated and exhibits characteristics expected of ligand-receptor interaction. The binding reaction has been adapted to a homogeneous chemiluminescence assay well-suited to HTS for antagonists of oligomer binding. Unlike high content, cell-based assays, the biochemical assay for binding to soluble receptors has the bandwidth and precision required for the primary screening of very large libraries of compounds. Parallel investigations of these SPM-Nanodiscs, separate from this project, are expected to identify the receptor protein(s). Our Approach to drug discovery follows a screening tree in which hits from the primary assay using SPM-Nanodiscs are validated in cell-based assays for binding and toxicity, first with synthetic oligomers and then with brain-derived oligomers. The Nanodisc HTS and secondary screens will be optimized at first using a small library and then greatly expanded. Hit-to-lead resources o the Northwestern Center for Molecular Innovation and Drug Discovery will be implemented as needed. The Aim, expected to be achieved by the end of two years, is to establish a fully functioning strategy for HTS of the very large libraries now available under the auspices of NIH. Results ultimately have strong potential for discovering lead compounds that target an underexploited but significant aspect of AD pathogenesis.